The overall goal of this proposal is to develop a novel therapy - prostaglandin E2 (PGE2) - to mitigate the effects of radiation on the hematopoietic system. This robust cellular system is disrupted and damaged by exposure to radiation, which results in cytopenias leading to life-threatening infections, anemia, and bleeding. The onset and extent of platelet loss predicts survival following total body irradiation. The majority of agents that have been developed and stockpiled for use as part of a radiological emergency are specifically targeted at the clinical consequences of white blood cell loss. Although much work has been done over the past decades, few agents have transitioned from bench to clinic. The collaborative studies of the Palis and Calvi labs within the University of Rochester's Center for Medical Countermeasures against Radiation have resulted in the development of robust mouse models of acute and late radiation injury. Our preliminary studies indicate that PGE2, delivered 48-72 hours after acute radiation exposure, mitigates the megakaryocyte lineage leading to more rapid platelet recovery. In addition, PGE2 acutely mitigates the number of phenotypic HSC. We hypothesize that PGE2 acts through the marrow microenvironment, specifically at the level of endothelial cells and macrophage populations, to mitigate radiation-induced injury of hematopoietic stem cells and megakaryocyte precursors. We will assess the effectiveness and mechanism of PGE2 mitigation of acute and late hematologic injury. Our joint studies have also identified a special population - 14 day old mice - as being particularly sensitive to relatively lw sublethal radiation exposure, since they develop not only a severe reduction in phenotypic HSCs but also late peripheral cytopenias. A better understanding of the differential response between pediatric and adult populations, both to radiation injury and any proposed agents, will be required to develop treatments with broad applicability. We will, therefore, also investigate the efficacy of PGE2 to mitigate late injury to the hematopoietic system of pediatric versus adult populations. Taken together, our proposed collaborative, mechanistic studies will bring forward PGE2, a promising new agent with an established safety profile, for use in mitigating both acute and late effects of radiation exposure.